Glaucoma Filtering Procedure Studies

We are investigating the ability of specific oxidative catalysts to modulate the scarring of a wound after a filtering procedure. We are attempting to see if a surgical sponge with these oxidative catalysts attached will keep a wound open by blocking fibrosis. The purpose of this research is to develop a method to block fibrosis so that an access channel for aqueous humor can be produced in cases of glaucoma that do not respond to other treatment modalities. At the moment, we have found that this material will block fibrosis in a rabbit eye. Future studies will involve covalently attaching the oxidative catalyst to a Molteno valve so the catalyst is permanently located at the site where the unwanted scar formation occurs.

Ocular Drug Design Center

Our collaborative drug design research program involves a combination of three different methods: 1) NMR spectroscopy and computer-assisted modeling used to determine the solution structure of substance P (SP) and new analogs and their interaction with the SP receptor; 2) organic synthesis techniques used to make new amino acids which will then be incorporated into new SP analogs based on modeling studies and the results of physiological assays; 3) different physiological and biological assays used to determine how the new SP analogs can interact with the SP receptor. Recent results show that small changes in the stereochemistry of SP around a single bond can be detected by the SP receptor and that these stereospecific changes can be used to detect different classes of SP receptors. One of these new compounds has been shown to stimulate a response at 1/10 the concentration necessary for SP. Based upon this information, we are now synthesizing a new molecule where the essential groups are locked into a specific orientation. Our long-term goal is to produce a SP molecule that is stable in a physiological environment and yet will readily activate a specific SP receptor.

Clinical Psychophysics

Clinical psychophysics broadly refers to the study of human visual abnormalities using psychophysical, electrophysiological, behavioral, and similar techniques. Our contribution has principally concerned three hereditary retinal disorders: retinitis pigmentosa, achromatopsia, and congenital stationary nightblindness. With regard to retinitis pigmentosa, our contribution has been in the understanding of the relationship between the cone degeneration and the ensuing photopic disorder. With regard to congenital stationary nightblindness, our principal contribution has been in the understanding of the photopic ERG b-wave. Our observation led to the hypothesis that the x-linked recessive form of CSNB was actually a disorder of the On-bipolar pathway. Our studies of achromatopsia are mentioned elsewhere in our web page.

PVR Studies

The growth factor FGF has been shown to be an excellent growth factor for endothelial cells and fibroblasts. Working with Tim Kogan, Ph.D., of Texas Biotechnology, Inc. (Houston, TX), we have developed an antisense DNA that will block the synthesis of the FGF receptor in cells in culture. In a collaborative study with ??, we have developed a rabbit model for proliferative vitreoretinopathy (PVR). We are now in the process of testing this model. We have shown that the antisense molecules are effective inhibitors of the growth of human retinal pigment epithelial cells in tissue culture. We have started experiments to see if the antisense molecules will block the growth of these cells in the animal model.

Low Vision

Low vision refers to the visual condition in which such everyday skills as reading a book, driving a car, threading a needle, and so forth are impaired. Our research in this field concerned two problems: First, how people with predominately night vision capability see in daylight illumination, and second, how people with a central visual scotoma read words. Our investigation of the first problem included studies concerned with visual improvements produced by dark glasses (Young, Krefman, and Fishman, 1982; Young, Krefman, Anderson and Fishman, 1983) as well as studies concerned with understanding the visual complaints of patients who lack the day vision system (Young and Price, 1985; Young, Price, and Harrison, 1987). Our research on the second problem developed a model for studying how people with a central scotoma read words. Our model involved visually normal observers placed under experimental conditions where they can only see with their rod vision (Chaparro and Young, 1989; Chaparro and Young, 1993).

Chaparro A and Young R: Reading with the rod visual system. Applied Optics 28:1110-1114, 1989.

Chaparro A and Young R: Reading with rods: The superiority of central vision for rapid reading. Invest Ophthalmol and Visual Sci 34:2341-2347, 1993.

Rockefeller Young, Ph.D.

Pterygia Studies

Pterygia are abnormal growths on the surface of the eye and are a common worldwide ophthalmologic problem in which vision may be impaired by the growth of tissue from the limbal region of the conjunctiva across the cornea. We have previously shown that pterygia result from an abnormal limbal epithelial stem cell that overexpresses p53 gene product probably due to a UV induced mutation in that gene. The current aim of this project is to determine whether metalloproteinases play a role in the ability of the mutated limbal stem cells to migrate onto and dissolve Bowman's layer and whether that role is different in limbal tumors.

Pupil Light Reflex

Although most visual information from the eye goes to the perceptual centers of the brain, some goes to the pretectum, an area that controls the diameter of the pupil in the eye. Professor Young and his colleagues hope to determine the functional characteristics of the visual pathway(s) that carry the information to the pretectum. Their evidence so far suggests the existence of multiple pathways that have stimulus-response characteristics not dissimilar to the retino-cortical phasic (M-) and tonic (P-) pathways. Their best guesses presently are that the pupillary visual pathway includes the ON- (Y-) type M-like cells and four types of P-like cells. The four types are red-on/green-off, green-on/red-off, blue-on/yellow-off, and yellow-on/blue-off.

Fang L and Young R: Temporal response characteristics of the pupillary visual pathway in humans. In preparation.

Rockefeller Young, Ph.D.

Secondary Cataract Studies

We have recently shown that the covalent attachment of selenium to a solid matrix will result in a biomaterial that will inactivate growth factors and block cellular growth. In particular, we have shown that we can inhibit the growth of lens epithelial cells. In collaboration with Dr. Stephen Kosto of Advanced Plasma Systems (St. Petersberg, Fl.) we have developed a technique to produce attachment sites on the surface of an intraocular lens (IOL). Using these treated lenses, we are covalently attaching selenium to an IOL to see if it will inhibit secondary cataract formation in a rabbit.

Substance P Studies

This research focuses on the mechanism by which peptides interact with cellular receptors to stimulate physiological events. One peptide currently under investigation is the neuropeptide substance P (SP). SP is eleven amino acids long and has been extensively studied by non-ocular scientists because of its many general physiological effects (smooth muscle contraction, inflammation, neurotransmission, blood vessel dilation, histamine release, and activation of the immune system). Studies in our lab have recently found that SP will stimulate epithelial cell growth and modulate the attachment of epithelial cells to their underlying matrix. Additional information implicates a key role for SP in healing ulcers. Studies on SP are investigating its potential to modify the attachment of epithelial cells to a cornea after wound healing. We are looking at both the strength of the attachment and the ultrastructure of the cornea after wounding followed by treatment with SP. This study is based on our findings that SP plays an important role in cellular attachment for epithelial cells and thus is probably the underlying cause of neurotrophic ulcers. Additionally, we are synthesizing new and novel analogs of SP in our Ocular Drug Design Center which will be tested in our model systems. We have recently produced an SP analog that has 10 times the activity of SP.

Use of Defensins as Preservatives for Cornea Transplants

Defensins are peptides that are potent antibiotics against gram negative and gram positive bacteria, as well as fungi and enveloped virus. We have shown that they are also capable of stimulating epithelial cell growth. The question is whether they would be harmful to the endothelial cells of the cornea if used as a preservative. Human donor corneas unsuitable for transplantation will be divided into two groups matched for age. Both control and test groups will be stored in identical nutritive media at 4¼ C. The test group will have a quantity of defensins previously shown to be microbicidal added to the media under sterile conditions. Both groups will then undergo periodic endothelial cell analysis using our Bio-Optics Eye Bank specular microscopic system. At the moment, we are testing the defensins on human corneal endothelial cells growing in culture.